1-65614586-T-A

Position:

• chr1-65614586-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002303.6(LEPR):​c.1996-1422T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 152,072 control chromosomes in the GnomAD database, including 4,517 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (4517 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.01

Genes affected

LEPR (HGNC:6554): (leptin receptor) The protein encoded by this gene belongs to the gp130 family of cytokine receptors that are known to stimulate gene transcription via activation of cytosolic STAT proteins. This protein is a receptor for leptin (an adipocyte-specific hormone that regulates body weight), and is involved in the regulation of fat metabolism, as well as in a novel hematopoietic pathway that is required for normal lymphopoiesis. Mutations in this gene have been associated with obesity and pituitary dysfunction. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. It is noteworthy that this gene and LEPROT gene (GeneID:54741) share the same promoter and the first 2 exons, however, encode distinct proteins (PMID:9207021).[provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6	c.1996-1422T>A		intron_variant		ENST00000349533.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11	c.1996-1422T>A		intron_variant		1	NM_002303.6	P4

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31855 AN: 151954 Hom.: 4514 Cov.: 32

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.0855

Gnomad EAS AF: 0.776

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.200

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.210 AC: 31876 AN: 152072 Hom.: 4517 Cov.: 32 AF XY: 0.218 AC XY: 16190 AN XY: 74330

Gnomad4 AFR AF: 0.153

Gnomad4 AMR AF: 0.242

Gnomad4 ASJ AF: 0.0855

Gnomad4 EAS AF: 0.775

Gnomad4 SAS AF: 0.128

Gnomad4 FIN AF: 0.347

Gnomad4 NFE AF: 0.187

Gnomad4 OTH AF: 0.205

Alfa AF: 0.202 Hom.: 432

Bravo AF: 0.205

Asia WGS AF: 0.381 AC: 1324 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.5
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4655555; hg19: chr1-66080269; COSMIC: COSV60755495; COSMIC: COSV60755495;